Immunogenetics of juvenile idiopathic arthritis: A comprehensive review

Abstract

Juvenile idiopathic arthritis (JIA) is the most common chronic inflammatory arthropathy of childhood. Juvenile idiopathic arthritis is believed to be a complex genetic trait influenced by both genetic and environmental factors. Twin and family studies suggest a substantial role for genetic factors in the predisposition to JIA. Describing the genetics is complicated by the heterogeneity of JIA; the International League of Associations for Rheumatology (ILAR) has defined seven categories of JIA based on distinct clinical and laboratory features. Utilizing a variety of techniques including candidate gene studies, the use of genotyping arrays such as Immunochip, and genome wide association studies (GWAS), both human leukocyte antigen (HLA) and non-HLA susceptibility loci associated with JIA have been described. Several of these polymorphisms (e.g. HLA class II, PTPN22, STAT4) are shared with other common autoimmune conditions; other novel polymorphisms that have been identified may be unique to JIA. Associations with oligoarticular and RF-negative polyarticular JIA are the best characterized. A strong association between HLA DRB1:11:03/04 and DRB1:08:01, and a protective effect of DRB1:15:01 have been described. HLA DPB1:02:01 has also been associated with oligoarticular and RF-negative polyarticular JIA. Besides PTPN22, STAT4 and PTPN2 variants, IL2, IL2RA, IL2RB, as well as IL6 and IL6R loci also harbor variants associated with oligoarticular and RF-negative polyarticular JIA. RF-positive polyarticular JIA is associated with many of the shared epitope encoding HLA DRB1 alleles, as well as PTPN22, STAT4 and TNFAIP3 variants. ERA is associated with HLA B27. Most other associations between JIA categories and HLA or non-HLA variants need confirmation. The formation of International Consortia to ascertain and analyze large cohorts of JIA categories, validation of reported findings in independent cohorts, and functional studies will enhance our understanding of the genetic underpinnings of JIA.

The epigenetics of PBC: The link between genetic susceptibility and environment

“…Besides that, some mechanisms remain largely unknown, such as causal nucleotide changes, rare genetic variants or the missing heritability sequencing [19][20][21]. Indeed, the use of GWAS have been very disappointing, i.e., it is likely that there are loci that have not been identified due to a lack of statistical significance; this is true not only of PBC, but also for a variety of other AIDs, many of which have been recently reviewed [22][23][24][25][26][27][28][29][30][31][32][33]. As a consequence, progress towards understanding disease mechanisms has been limited by difficulties in assigning a molecular function to the vast majority of GWAS hits that do not affect protein-coding sequences.…”

An immunome perturbation is present in juvenile idiopathic arthritis patients who are in remission and will relapse upon anti-TNFα withdrawal

“…Functional gene enrichment analysis (DAVID) of JIA relapse (n=6) or remission (n=6) patients versus healthy individuals (n=3) identified 5 common disease centric pathways that persisted from prior to after withdrawal of therapy (online supplementary Figure S5 and Table S4-5). Dysregulation in UBE2L3, IL-6, STAT4, TYK2, TNFAIP3 and PTPN2 were found in both relapse and remission individuals, have been previously associated with JIA [21,22]. We examined through Cytoscape and Reactome database for the gene associations involved in the 5 pathways (Figure 5A-E Table S3 and 6).…”

Therapeutic Antibody‐Based Drugs in the Treatment of Human Inflammatory Disorders

“…Furthermore, the presence of TNF, IL-6 and IL-1β strongly points to the involvement of macrophages-particularly type-I macrophages (M1 MØ) which, when activated, produce this combination of cytokines. Interestingly, a polymorphism in macrophage migration-inhibitory factor (MIF) has been found to be associated with SJIA [15,16]. Indeed, the diverse presentation of juvenile arthritis suggests that there is still much more to learn about the aetiology of arthritis in children.…”